Lung cancer is one of the major causers of cancer-related deaths in the world. There are two primary types of lung cancers: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) (Carney, (1992a) Curr. Opin. Oncol. 4:292-8). Small cell lung cancer accounts for approximately 25% of lung cancer and spreads aggressively (Smyth et al. (1986) Q J Med. 61: 969-76; Carney, (1992b) Lancet 339: 843-6). Non-small cell lung cancer represents the majority (about 75%) of lung cancer and is further divided into three main subtypes: squamous cell carcinoma, adenocarcinoma, and large cell carcinoma (Ihde and Minna, (1991) Cancer 15: 105-54). In recent years, much progress has been made toward understanding the molecular and cellular biology of lung cancers. Many important contributions have been made by the identification of several key genetic factors associated with lung cancers. However, the treatments of lung cancers still mainly depend on surgery, chemotherapy and radiotherapy. This is because the molecular mechanisms underlying the pathogenesis of lung cancers remain largely unclear.
A recent hypothesis suggests that lung cancer is caused by genetic mutations of at least 10 to 20 genes (Sethi, (1997) BMJ. 314: 652-655). One of the future strategies for the prevention and treatment of SCLC will be focused on the elucidation of the genes associated with protooncogene, in particular, the c-kit gene. This suggestion is based on the evidence that the c-kit gene was found to be expressed preferentially in SCLC (Sekido et al. (1991) Cancer Res 51:2416-9), which indicates an important role of the c-kit gene in the tumorigenic process of SCLC. One of the genes associated with the c-kit is the megakaryocyte-associated tyrosine kinase (MATK) (Jhun et al. (1995) J Biol Chem 270: 9661-6; Price et al. (1997) J Biol Chem 272:5915-20). MATK, a protein tyrosine kinase containing the Src homology 2 and 3 (SH2 and SH3) domains, was also termed Csk-homologous kinase (CHK) based on its high sequence similarity to the Csk tyrosine kinase. The functional roles of MATK have been shown to be involved in cell proliferation and differentiation, and chromosome dynamics (Avraham et al. (1995) J Biol Chem 270:1833-42; Zrihan-Licht et al. (1998) J Biol Chem 273:4065-72; Yamashita et al. (1999) J Biol Chem 274:15059-65; Yamaguchi et al. (2001) J Cell Sci 114:1631-41). The genetic localization analysis has assigned MATK to chromosome 19p13.3 (Avraham et al. (1995) J Biol Chem 270:1833-42). Several studies have shown that the abnormality of chromosome 19 is associated with lung tumor susceptibility (Johansson et al. (1995) Cancer Genet Cytogenet 80:85-6; Dang et al. (2000) J Natl Cancer Inst 92:1355-7; Wang et al. (2000) Clin Cancer Res 6:2988-93; Sobottka et al. (2000) J Neurooncol 49:187-95). Interestingly, the gene variants of a chromosome 19 gene, C-CAM1, were shown to be involved in lung tumorigenesis (Wang et al. (2000) Clin Cancer Res 6:2988-93) raising the possibility that the gene variants of MATK may also be involved in the tumorigenic process of SCLC. Therefore, it is believed that the discovery of gene variants of MATK may serve as important targets for diagnostic markers of SCLC.